Kaposi's sarcoma (KS) is the most common malignancy in patients with acquired immunodeficiency syndrome (AIDS) in the United States. Kaposi's Sarcoma is a multifocal neoplasm, consisting of several cell types and abundant angiogenesis. The tumor cell is believed to be a spindle-shaped cell and is usually considered to be of endothelial origin (Rutgers et al. (1986) Am. J. Pathol. 122: 493-499). However, its precise cellular origin and even its classification as a true monoclonal malignancy versus a polyclonal hyperplasia have remained elusive (Shaw et al. (1984) Science 226: 1165-1171; Holden et al. (1989) J. Invest. Dermatol. 93: 119S-124S; Hashimoto et al. (1987) Pathol. Res. Pract. 182: 658-668). The isolation of a Kaposi's sarcoma cell line would aid in elucidating the mechanism of KS induction and pathogenesis.
A major problem in treating Kaposi's sarcoma is that most or all of the known therapies have serious adverse effects, including myelotoxicity and neurotoxicity (see, e.g. Northfeldt et al. (1991) Hematology/Oncology Clinics of North America 5: 297-310, which is incorporated herein by reference). These therapies can also induce immunosuppression, compounding the pre-existing immunodeficiency that is usually present in AIDS patients. Thus, a great need exists for a system for testing anti-Kaposi's sarcoma therapies without having to subject human patients to the trial and error process of optimizing combinations and dosages of therapeutic agents or procedures.
The isolation of an immortal malignant Kaposi's sarcoma cell line would provide such a system. Such a cell line would provide a system for assaying antitumor drugs and other therapies that can be useful in reducing growth and metastatic spread of KS cells in vivo. A malignant KS cell line would also allow the development of novel antitumor therapies, such as the production of a KS-specific monoclonal antibody that is useful for diagnosis or for targeting therapeutic drugs. Studies of the hormonal, immunological, virological, and cytokine-mediated factors that influence the development and metastasis of malignancies would also be facilitated by the development of a malignant KS cell line.
No previously isolated KS cell line is capable of continuous growth absent growth factors and is also tumorigenic. Nakamura et al. ((1988) Science 242: 426-430, which is incorporated herein by reference) previously reported KS cell strains that required growth factors such as those contained in conditioned medium (CM) from retrovirus-infected CD4.sup.+ T-lymphocytes for growth. These KS cell strains survived for at least 236 days when grown in conditioned medium, but for only 36 days when grown in the absence of conditioned medium. Subcutaneous injection of these KS cells into nude mice induced angiogenic lesions, however the lesions regressed after 6 days and no tumors formed. Cells from these lesions were all of mouse origin, as determined by chromosome analysis.
Tsai et al. isolated a Kaposi's sarcoma-like cell line from simian AIDS with retroperitoneal fibromatosis (RF), but this line does not induce tumor growth in mice (Tsai et al. United States and Canadian Academy of Pathology Annual Meeting, Mar. 5-10, 1989, p. 585).
Philip et al. isolated the KSC-8 cell strain from a Kaposi's sarcoma patient (Philip et al. (1991) J. Acquired Immune Deficiency Syndromes, 4: 1254-1257, which is incorporated herein by reference). KSC-8 cells have multiple large chromosomal rearrangements and are pseudoploid. This strain induced tumors after intraperitoneal injection into nude mice, but there is no indication of how long KSC-8 can survive in culture. Moreover, and unlike the cells of this invention, the KSC-8 cells lack Ulex europaeus agglutinin 1 (UEA-1) binding ability. Thus, the Kaposi's sarcoma phenotype of these cells cannot be conclusively established.
The cell line disclosed herein, in contrast to those cell strains previously reported, fulfills the needs discussed above, and others. The cell line provides a means for testing anti-Kaposi's sarcoma therapies in vitro, or in a model animal system, rather than in a human patient. This allows therapies to be tested and dosages to be optimized before testing the therapies in humans. The cell line also provides a means of developing novel antitumor therapies and also serves as a source of known and novel growth factors. Also, the cell line will facilitate studies of factors that influence the development and metastasis of malignancies.